当前位置: X-MOL 学术Cell Death Dis. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Necroptosis is active and contributes to intestinal injury in a piglet model with lipopolysaccharide challenge
Cell Death & Disease ( IF 8.1 ) Pub Date : 2021-01-11 , DOI: 10.1038/s41419-020-03365-1
Yulan Liu 1 , Qiao Xu 1 , Yang Wang 1 , Tianzeng Liang 1 , Xiangen Li 1 , Dan Wang 1 , Xiuying Wang 1 , Huiling Zhu 1 , Kan Xiao 1
Affiliation  

Necroptosis, a newly discovered form of programmed cell death that combines the features of apoptosis and necrosis, is important in various physiological and pathological disorders. However, the role of necroptosis on intestinal injury during sepsis has been rarely evaluated. This study aimed to investigate the presence of necroptosis in intestinal injury, and its contribution to intestinal injury in a piglet model challenged with Escherichia coli lipopolysaccharide (LPS). Firstly, a typical cell necrotic phenomenon was observed in jejunum of LPS-challenged pigs by transmission electron microscope. Protein expression of necroptosis signals including receptor-interacting protein kinase (RIP) 1, RIP3, and phosphorylated mixed-lineage kinase domain-like protein (MLKL), mitochondrial proteins including phosphoglycerate mutase family member 5 (PGAM5) and dynamin-related protein 1 (DRP1), and cytoplasmic high-mobility group box 1 (HMGB1) were time-independently increased in jejunum of LPS-challenged piglets, which was accompanied by the impairment of jejunal morphology, and digestive and barrier function indicated by lower activities of jejunal disaccharidases and protein expression of jejunal tight junction proteins claudin-1 and occludin. Pro-inflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, and IL-6 were also dynamically induced in serum and jejunum of piglets after LPS challenge. Moreover, pretreatment with necrostatin-1 (Nec-1), an specific inhibitor of necroptosis, inhibited necroptosis indicated by decreased necrotic ultrastructural changes and decreased protein expression of RIP1, RIP3, and phosphorylated MLKL as well as PGAM5, DRP1, and cytoplasmic HMGB1. Nec-1 pretreatment reduced jejunal morphological injury, and improved digestive and barrier function. Nec-1 pretreatment also decreased the levels of serum and jejunal pro-inflammatory cytokines and the numbers of jejunal macrophages and monocytes. These findings indicate for the first time that necroptosis is present and contributes to LPS-induced intestinal injury. Nec-1 may have a preventive effect on intestinal injury during sepsis.



中文翻译:

坏死性凋亡是活跃的,并有助于脂多糖挑战的仔猪模型中的肠道损伤

坏死性凋亡是一种新发现的程序性细胞死亡形式,它结合了细胞凋亡和坏死的特征,在各种生理和病理疾病中很重要。然而,很少评估坏死性凋亡对脓毒症期间肠道损伤的作用。本研究旨在调查肠道损伤中坏死性凋亡的存在,及其对感染大肠杆菌的仔猪模型肠道损伤的影响脂多糖(LPS)。首先,通过透射电子显微镜在LPS攻击的猪的空肠中观察到典型的细胞坏死现象。坏死性凋亡信号的蛋白表达,包括受体相互作用蛋白激酶 (RIP) 1、RIP3 和磷酸化混合谱系激酶结构域样蛋白 (MLK​​L),线粒体蛋白包括磷酸甘油酸变位酶家族成员 5 (PGAM5) 和动力蛋白相关蛋白 1 ( DRP1) 和细胞质高迁移率族框 1 (HMGB1) 在 LPS 攻击仔猪的空肠中随时间独立地增加,伴随着空肠形态的损害,以及由空肠双糖酶和空肠紧密连接蛋白claudin-1和occludin的蛋白表达。LPS 攻击后仔猪的血清和空肠中也动态诱导了促炎细胞因子,包括肿瘤坏死因子-α (TNF-α)、白细胞介素 (IL)-1β 和 IL-6。此外,用坏死性凋亡的特异性抑制剂 necrostatin-1 (Nec-1) 预处理可抑制坏死性凋亡,表现为坏死超微结构变化减少,RIP1、RIP3 和磷酸化 MLKL 以及 PGAM5、DRP1 和细胞质 HMGB1 的蛋白质表达减少。Nec-1 预处理减少了空肠形态损伤,并改善了消化和屏障功能。Nec-1 预处理还降低了血清和空肠促炎细胞因子的水平以及空肠巨噬细胞和单核细胞的数量。这些发现首次表明存在坏死性凋亡并导致 LPS 诱导的肠道损伤。

更新日期:2021-01-11
down
wechat
bug